Regulation of tumor necrosis factor-α and tumor necrosis factor converting enzyme in human osteoarthritis

Abstract

A snake venom-like protease isolated by a differential display screen between normal and osteoarthritis (OA)-affected cartilage (designated as cSVP) has a cDNA sequence identical to tumor necrosis factor (TNF)α convertase enzyme (TACE) and belongs to the adamalysin group of proteases. It has unique structural properties and when expressed in baculovirus, cleaves preferentially proTNFα to TNFα. The OA-affected cartilage has upregulated mRNA for TNFα and TACE as compared to normal cartilage. TNFα and TACE regulate inflammatory mediators in OA-affected cartilage which can be inhibited by both soluble TNFα receptors and inhibitors of TACE. These experiments demonstrate a functional paracrine/autocrine role of TNFα in OA- affected cartilage that is modulated by upregulated levels of chondrocyte- derived TACE.